Precise Tacrolimus Dose Adjustments in Kidney Transplant patients from Industrial Workforce Considering CYP3A5 Genotyping Beyond Therapeutic Drug Monitoring

The average bioavailability of Tacrolimus is merely 25%and it varies, ranging from 5 to 90% [5]. About 99% of Tacrolimus binds to erythrocytes after entering the systemic circulation [5]. It is primarily metabolized by the CYP3A enzyme system, which includes CYP3A5, CYP3A4, CYP3A7. and CYP3A43 which is expressed in small intestine, liver and kidney [5]. Compared with CYP3A5, the catalytic efficiency of CYP3A4 was relatively low [5]. The CYP3A7 has little influence on the metabolism of Tacrolimus, while the role of CYP3A43 is unclear [5]. The total body clearance of Tacrolimus is relatively low, around 0.06 L/(hâ‹…kg) [5]-. The half-life is long and variable, ranging from 4 to 41 h (about 12 h on average) [5]. Approximately 95% of Tac metabolites are excreted by bile, and urinary excretion is only about 2% [5]. Only 0.5% of the original drug is excreted through urine and feces [5]. Polymorphisms of cytochrome P450 3A5 (CYP3A5) enzyme significantly affects tacrolimus metabolism [6]. The most notable alleles are CYP3A5 *1/*1 (Extensive metabolizer) or *1/*3 alleles (Intermediate metabolizer), which result in the expression of functional CYP3A5 and lead to higher tacrolimus clearance [6]. Patients with these alleles require higher doses of tacrolimus to achieve therapeutic drug levels compared to individuals with the CYP3A5 *3/*3 genotype (poor metabolizer), who are non-expressers of the enzyme and thus have reduced clearance [6]. Despite its efficacy, the clinical management of tacrolimus is challenging due to its narrow therapeutic index [7]. There is significant inter and intra-patient variability in pharmacokinetics and pharmacodynamics [7]. The attributable factors are age, weight, organ function, co-medications and genetic polymorphisms on drug-metabolizing enzymes and transporters [7]. Given these complexities, Therapeutic Drug Monitoring (TDM) of tacrolimus is essential to ensure that optimal blood concentrations remain within the therapeutic range, thus minimizing the risks of rejection and toxicity [8]. The study integrating dual monitoring with genotype and TDM are already available for the dosage adjustment which enhances the precision of dosing regimens. But such combined studies in patients from Industrial workforce are shortly reported.